RANKL is a member of the tumor necrosis factor (TNF) cytokine family that is a ligand for osteoprotegerin, and functions as a key factor for osteoclast differentiation, activation and survival. Targeted disruption of the related gene in mice leads to severe osteopetrosis and a lack of osteoclasts. These deficient mice exhibited defects in early differentiation of T and B lymphocytes, and fail to form lobulo-alveolar mammary structures during pregnancy.
The balance between RANKL, as a principle activator of osteoclast differentiation and activity, and its decoy ligand OPG has been shown to be the primary regulator of bone resorption. RANKL has been further validated as a mediator and biomarker of bone destruction that can be independent of coexisting cartilage damage and inflammation in arthritis.
Modulation of RANKL and/or OPG may therefore be beneficial in treatment of disorders implicated in osteoclast differentiation and/or activity, including bone regulation (e.g., resorption, remolding and/or growth). Suppression or inhibition of RANKL may be therapeutic in a range of other indications as well, including (but not limited to): glucocorticoid-induced and postmenopausal osteoporosis; reduction in bone erosions in rheumatoid arthritis, psoriatic arthritis and other systemic inflammatory diseases; increase in bone mass in patients treated with aromatase inhibitors or androgen deprivation therapy; prevention and treatment of bony metastases in solid tumors and multiple myeloma; and reduction in arterial plaque progression and rupture in atherosclerosis.
Overproduction of RANKL is implicated in a variety of bone diseases, such as rheumatoid arthritis and psoriatic arthritis. RANKL inhibitors (such as denosumab) have been proposed to treat osteoporosis in post-menopausal women. Further, inhibition of RANKL has been examined as a treatment for metastases from a variety of solid tumors and lytic bone lesions in multiple myeloma. For example, metastatic tumor cells may commandeer osteoblasts and other cells in bone to produce RANKL; the tumor cells then uses the resident osteoclasts to breakdown bone matrix and establish metastatic foci and also allow the metastases to grow.
Currently there are a number of pharmacological agents being examined to inhibit RANKL, increase OPG, or increase the OPG/RANKL ratio. For example, as mentioned above, Denosumab is an anti-RANKL antibody that inhibits RANKL. Unfortunately, there are many disadvantages to these therapies, including undesirable side effects and patient compliance. Thus, there is a need for a non-pharmacological therapy to modulate RANKL, OPG and/or OPG/RANKL ratio.
As described in detail herein, the inventors have surprisingly discovered that stimulation of the vagus nerve profoundly and significantly modulates RANKL, OPG and/or OPG/RANKL ratio. Although stimulation of the vagus nerve has been previously described, this is the first time that such stimulation (and particularly electrical stimulation) has been suggested to modulate RANKL.
For example, stimulation of the cholinergic anti-inflammatory pathway (CAP) has been shown to modulate inflammation. CAP is a physiologic regulator of systemic inflammation which utilizes the vagus nerve to reflexively reduce inflammatory responses. Brief, intermittent neurostimulation of the vagus nerve (NCAP) has been shown to be effective in a variety of animal models of acute inflammation (Nature Rev Immunol 2009; 9:418). NCAP using implantable stimulation devices also holds promise as a potential therapeutic approach for chronic human inflammatory diseases. To date, however, the biological pathways affected by NCAP have not implicated RANKL or bone morphology.
For example, US 2006/0178703 to Huston et al. describes treatment of inflammation and inflammatory disorders (including rheumatoid arthritis) by electrical stimulation of the vagus nerve. Although Huston broadly teaches the stimulation of the vagus nerve (including using an implantable stimulator), this references does not optimize the stimulation with respect to osteoprotegerin (e.g., RANKL or OPG).
By targeting the stimulation parameters specific to RANKL/OPG, the methods and devices described herein may avoid potentially undesirable and unnecessary side effects of pharmacological intervention to modulate RANKL/OPG, and may provide for the first time, an implantable, electrical or mechanical devices for modulating RANKL/OPG; non-implantable electrical and mechanical modulation means are also contemplated and described. This data has been prepared using a rodent animal model to examine the effect of vagus stimulation in a rat model, examining bone morphology generally and RANKL/OPG specifically.